Anthrax is a well-characterized infectious disease caused by the sporulating bacteria Bacillus anthracis. The disease is historically associated with animal infections, especially herbivores such as cows, sheep, and goats, and is not typically found in humans. However, humans working with animal products where infection occurs are at risk of contracting anthrax. Some regions of the Middle East and sub-Saharan Africa are hyperendemic for anthrax, though the organism can often be found in many areas of the world. The disease manifests in three different ways: cutaneous, gastrointestinal and inhalation anthrax result from exposure of an open wound to spores, ingesting spores in contaminated meat products, and inhaling spores, respectively. While cutaneous anthrax has a fatality rate of up to 25 percent, gastrointestinal or inhalation anthrax results in nearly 100 percent fatalities. Definitive diagnosis of anthrax infection often comes too late to provide resuscitative care.
The principal virulence factor of B. anthracis is a multi-component toxin secreted by the organism. The toxin consists of three proteins designated protective antigen (PA), lethal factor (LF) and edema factor (EF), which are encoded by the genes pag, lef, and cya, respectively. PA is a 735 amino acid protein of molecular weight 83 kDa. It binds to the anthrax toxin receptor (ATR) on the mammalian cell surface, and subsequently undergoes a furin-mediated cleavage to yield a 63 kDa receptor-bound product. The 63 kDa PA fragment forms a heptameric complex on the cell surface which is capable of interacting with either LF or EF, and this complex is subsequently internalized. LF is a zinc metalloprotease that cleaves several isoforms of MAP kinase kinase, thereby disrupting signal transduction events within the cell, eventually leading to cell death. LF is considered responsible for the lethal outcome of anthrax infection. EF is a calmodulin-dependent adenylate cyclase that causes deregulation of cellular physiology, leading to clinical manifestations that include edema. PA and LF together are referred to as lethal toxin.
The CDC lists anthrax as a category A disease agent and estimates the cost of an anthrax attack to exceed $26 billion per 100,000 persons exposed. Presently, the only vaccine licensed for human use in the U.S., Biothrax (formerly Anthrax vaccine adsorbed, or AVA), is an aluminum hydroxide-adsorbed, formalin-treated subunit vaccine based on protective antigen, PA. It is delivered by subcutaneous injection and induces immunity against lethal toxin secreted by the bacillus. The vaccine is produced from the filtered culture supernatant fraction of the V770-NP1-R strain of B. anthracis. The production process is complex. There is variation from batch-to-batch in vaccine preparation lots, and the precise composition of the vaccine is undetermined. Furthermore, since alum is included as an adjuvant with the current vaccine, a cold chain must be maintained during vaccine storage and distribution, adding inconvenience and cost. The vaccine is administered by injection, which can complicate the logistics of mass treatments. In addition to the immunogenic protective antigen (PA), the vaccine contains trace amounts of edema factor (EF) and lethal factor (LF) that may contribute to the local reactions seen in 5-7% of vaccine recipients, or reported to be causing toxic side-effects.
Anthrax has become a serious threat due to its potential use in bioterrorism and recent outbreaks among wildlife in the United States. Concerns regarding vaccine purity, the current requirement for multiple injections followed by boosters, and a limited supply of vaccine underscore the urgent need for an improved vaccine. There is a clear need and urgency for an improved vaccine for anthrax and for improved production methods that allow for mass-production at reasonable cost.